Challenges associated with the integration of immuno-oncology agents in clinical practice.

BACKGROUND: The availability of new immuno-oncology therapeutics markedly impacts oncology clinicians' treatment decision-making. To effectively support healthcare professionals (HCPs) in their practice, it is important to better understand the challenges and barriers that can accompany the introduction of these agents. This study aimed to establish the types and causes of clinical challenges posed by the introduction of new immuno-oncology agents. METHODS: The mixed-methods design included qualitative in-depth interviews and group discussions with HCPs, in which participants discussed clinical challenges and potential underlying reasons for these challenges. Qualitative findings informed a quantitative survey. This survey investigated the extent and distribution of challenges using HCPs' self-rating of knowledge, skill, confidence, and exposure to system-level effects. These two phases were conducted sequentially with distinctly stratified samples of oncologists, nurse practitioners (NPs), physician assistants (PAs), pathologists, clinical pharmacists, interventional radiologists, rheumatologists, pulmonologists, and emergency department physicians. Participants were from the United States and had various levels of clinical experience and represented both academic and community-based settings. RESULTS: The final sample included 107 HCPs in the qualitative phase and 554 in the quantitative phase. Analyses revealed clinical challenges related to the use of pharmacodiagnostics. For example, 47% of pathologists and 42% of oncologists reported skill gaps in identifying the appropriate marker and 46% of oncologists, 61% of PAs, 66% of NPs, 74% of pulmonologists and 81% of clinical pharmacists reported skill gaps in selecting treatment based on test results. Challenges also emerged regarding the integration of immuno-oncology agents, as oncologists, rheumatologists, pulmonologists, clinical pharmacists, PAs, and NPs reported knowledge gaps (74-81%) of the safety profiles of recently approved agents. In addition, 90% of clinical pharmacists reported skill gaps weighing the risks and benefits of treating patients with immuno-oncology agents while affected by lupus. Finally, patient communication challenges were identified: HCPs reported difficulties discussing essential aspects of immunotherapy to patients as well as how they might compare to other types of therapies. CONCLUSION: The challenges highlighted in this study reveal substantial educational gaps related to the integration of immuno-oncology agents into practice for various groups of HCPs. These findings provide a strong base of evidence for future educational initiatives.

Management of Immune-Related Adverse Events in Patients Treated With Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline.

PURPOSE: To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with chimeric antigen receptor (CAR) T-cell therapy. METHODS: A multidisciplinary panel of medical oncology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to develop the guideline. Guideline development involved a systematic literature review and an informal consensus process. The systematic review focused on evidence published from 2017 to 2021. RESULTS: The systematic review identified 35 eligible publications. Because of the paucity of high-quality evidence, recommendations are based on expert consensus. RECOMMENDATIONS: The multidisciplinary team issued recommendations to aid in the recognition, workup, evaluation, and management of the most common CAR T-cell-related toxicities, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, B-cell aplasia, cytopenias, and infections. Management of short-term toxicities associated with CAR T cells begins with supportive care for most patients, but may require pharmacologic interventions for those without adequate response. Management of patients with prolonged or severe CAR T-cell-associated cytokine release syndrome includes treatment with tocilizumab with or without a corticosteroid. On the basis of the potential for rapid decline, patients with moderate to severe immune effector cell-associated neurotoxicity syndrome should be managed with corticosteroids and supportive care.Additional information is available at www.asco.org/supportive-care-guidelines.

Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.

PURPOSE: To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitor (ICPi) therapy. METHODS: A multidisciplinary panel of medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to update the guideline. Guideline development involved a systematic literature review and an informal consensus process. The systematic review focused on evidence published from 2017 through 2021. RESULTS: A total of 175 studies met the eligibility criteria of the systematic review and were pertinent to the development of the recommendations. Because of the paucity of high-quality evidence, recommendations are based on expert consensus. RECOMMENDATIONS: Recommendations for specific organ system-based toxicity diagnosis and management are presented. While management varies according to the organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, except for some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert ≤ grade 1. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids. Corticosteroids should be tapered over the course of at least 4-6 weeks. Some refractory cases may require other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, except for endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines.

Management of Pneumonitis and Neuropathy in Patients Receiving PD-1-Based Therapy for Non-Small-Cell Lung Cancer.

Immunotherapy with programmed cell death-1 (PD-1) receptor and programmed death ligand 1 (PD-L1) inhibitors has improved outcomes for certain patients with advanced lung cancer. As use of these therapies has expanded in first-line settings, in patients with different histologies, and in combinations with chemotherapeutic and targeted agents, more patients with lung cancer may benefit from these therapies. However, with expanded use comes greater potential exposure to the immune-related adverse events (irAEs) associated with these immune checkpoint inhibitors (ICIs). This article uses two case examples to illustrate the presentation, evaluation, and management of pulmonary and neurologic symptoms in two patients receiving PD-1-based therapy for non-small-cell lung cancer. These cases illustrate the challenges associated with recognizing pneumonitis and neuropathy in patients receiving ICIs for lung cancer. Although pneumonitis and neuropathy are relatively rare irAEs, they can have devastating or even fatal outcomes if not promptly recognized and managed appropriately. Specific use of guideline-based, multidisciplinary management is emphasized, as illustrated in the Immuno-Oncology Essentials Care Step Pathways.

PD-1/PD-L1 Inhibitors for Non-Small Cell Lung Cancer: Incorporating Care Step Pathways for Effective Side-Effect Management.

Programmed cell death protein 1 receptor and programmed cell death ligand 1 (PD-L1) inhibitors are immune checkpoint inhibitors (ICIs) that provide a survival benefit for select patients with advanced non-small cell lung cancer (NSCLC). Nivolumab, pembrolizumab, and atezolizumab are second-line therapies for advanced NSCLC after chemotherapy failure. Pembrolizumab and atezolizumab are also approved as first-line treatment for advanced NSCLC, and durvalumab is a PD-L1 inhibitor indicated as consolidation therapy in individuals with locally advanced NSCLC. The novel mechanism of action of these agents provides clear efficacy benefits to many NSCLC patients without good alternatives, but it may also result in unique immune-related adverse events that many health-care providers are unfamiliar with or uncertain about how to diagnosis and manage. Highlighting the resources of the Immuno-Oncology Essentials Initiative, particularly the Care Step Pathways (CSPs), this article addresses the role of the advanced practice provider in administration, side-effect identification and management, and education of patients with advanced NSCLC receiving ICI therapy. The diagnosis and management of pneumonitis, hypophysitis, diabetes mellitus, and arthralgias/myalgias are examined in detail, addressing special considerations in the NSCLC population.

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC).

Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for over 85% of all cases. Until recently, chemotherapy - characterized by some benefit but only rare durable responses - was the only treatment option for patients with NSCLC whose tumors lacked targetable mutations. By contrast, immune checkpoint inhibitors have demonstrated distinctly durable responses and represent the advent of a new treatment approach for patients with NSCLC. Three immune checkpoint inhibitors, pembrolizumab, nivolumab and atezolizumab, are now approved for use in first- and/or second-line settings for selected patients with advanced NSCLC, with promising benefit also seen in patients with stage III NSCLC. Additionally, durvalumab following chemoradiation has been approved for use in patients with locally advanced disease. Due to the distinct features of cancer immunotherapy, and rapid progress in the field, clinical guidance is needed on the use of these agents, including appropriate patient selection, sequencing of therapies, response monitoring, adverse event management, and biomarker testing. The Society for Immunotherapy of Cancer (SITC) convened an expert Task Force charged with developing consensus recommendations on these key issues. Following a systematic process as outlined by the National Academy of Medicine, a literature search and panel voting were used to rate the strength of evidence for each recommendation. This consensus statement provides evidence-based recommendations to help clinicians integrate immune checkpoint inhibitors into the treatment plan for patients with NSCLC. This guidance will be updated following relevant advances in the field.

Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management.

Agents that modulate immune checkpoint proteins, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death receptor-1 (PD-1), have become a mainstay in cancer treatment. The clinical benefit afforded by immune checkpoint inhibitors can be accompanied by immune-related adverse events (irAE) that affect the skin, gastrointestinal tract, liver, and endocrine system. The types of irAEs associated with immune checkpoint inhibitors are generally consistent across tumor types. Immune-related endocrine events can affect the pituitary, thyroid, and adrenal glands, as well as other downstream target organs. These events are unique when compared with other irAEs because the manifestations are often irreversible. Immune-related endocrine events are typically grade 1/2 in severity and often present with non-specific symptoms, making them difficult to diagnose. The mechanisms underlying immune-related target organ damage in select individuals remain mostly undefined. Management includes close patient monitoring, appropriate laboratory testing for endocrine function, replacement of hormones, and consultation with an endocrinologist when appropriate. An awareness of the symptoms and management of immune-related endocrine events may aid in the safe and appropriate use of immune checkpoint inhibitors in clinical practice.

Perceptions of roles, practice patterns, and professional growth opportunities: broadening the scope of advanced practice in oncology.

Broadening the scope of advanced practice providers (APPs) has been offered as a solution to increasing healthcare costs, workforce shortage, and increased demand. To understand present scope and barriers to broadening it, the authors describe the perceptions and practice patterns of APPs. This cross-sectional study used a computerized self-report survey of 32 targeted nurse practitioners and physician assistants employed in the cancer center of an urban teaching hospital; 31 were included in the quantitative analyses. Survey items covered education and training background, expertise, professional resources and support, duties, certification, and professional development. Respondents practiced in a variety of oncology specialty areas, but all had advanced degrees, most held specialty certifications, and 39% had attended a professional or educational meeting within the last year. They spent a majority of their time on essential patient-care activities, but clerical duties impeded these; however, 64% reported being satisfied with the time they spent with patients and communicating with collaborating physicians. A model of advanced oncology practice needs to be developed that will empower APPs to provide high-quality patient care at the fullest extent of their knowledge and competence.

Evaluation of irinotecan plus paclitaxel in patients with advanced non-small cell lung cancer.

PURPOSE: We conducted a phase II study to evaluate the efficacy and safety of the combination of irinotecan and paclitaxel in patients with advanced stage non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were eligible if they had histologically confirmed chemotherapy naïve stage IV NSCLC or stage IIIB disease that was not suitable for combined modality therapy. Patients were treated with irinotecan 50 mg/m2 and paclitaxel 75 mg/m2 on days 1 and 8 of a 21-day cycle. If the patient did not experience >grade 1 toxicity during the first cycle, the dose of irinotecan could be escalated to 60 mg/m(2). Patients were evaluated for tumor response rate, time to progression (TTP), overall survival (OS) and toxicity. RESULTS: Twenty-three eligible patients were treated. Two (9%) patients achieved a partial response. Eight patients (35%) had stable disease. The median number of cycles given per patient was four (range 1-29). The major toxicities were grade >or=3 neutropenia (26%) and grade 3 diarrhea (5%). The median time to progression was 2.8 months (range 0.5-21.8 months) for all patients and 4.3 months for the patients who had either stable disease or a partial response. The median overall survival was 9.2 months (range 0.5-40 months). The one- and two-year survival rates were 39% and 13%, respectively. CONCLUSION: The combination of irinotecan and paclitaxel is safe in advanced NSCLC and affords a survival similar to other non-platinum as well as platinum-based doublets. However, this combination does not have sufficient activity to justify further study in an unselected population. If biomarkers are developed that can guide the selection of chemotherapy in an individual patient, there may be a rationale for further evaluation of this regimen.

Phase I dose escalation trial of weekly docetaxel plus irinotecan in patients with advanced cancer.

Background. Docetaxel and irinotecan have additive or synergistic activity in vitro and in vivo as well as differing toxicities and unique mechanisms of action. We conducted a phase I trial to determine the maximum-tolerated dose of docetaxel and irinotecan given on a weekly schedule. Methods. Eligible patients had advanced, incurable, solid tumors. Docetaxel was administered as a 1-hour infusion and escalated over four dose levels (25, 30, 35, and 40 mg/m(2)) followed by irinotecan administered over 30 minutes at a fixed dose of 50 mg/m(2). Treatment was administered weekly for four weeks followed by two weeks of rest. To improve tolerability, the schedule was modified to weekly administration for two weeks with one week of rest, and irinotecan was escalated over 3 dose levels (55, 60, and 65 mg/m(2)) with docetaxel fixed at 35 mg/m(2). Results. Forty-four patients were treated and the most common dose-limiting toxicity was diarrhea observed in 11% of patients. Severe neutropenia was rare (grade 4: 2%, grade 3: 23%). Other nonhematologic toxicities included nausea/vomiting, dehydration and fatigue. Partial responses occurred in two patients with pancreatic cancer, and one patient each with non-small cell lung and esophageal cancer. Conclusions. Weekly docetaxel and irinotecan is a promising non-cisplatin doublet with preliminary evidence of activity in advanced solid tumors. Diarrhea is the predominant dose-limiting toxicity but unlike the every 3 weeks schedule myelosuppression is modest. The recommended phase II doses are docetaxel 35 mg/m(2) and irinotecan 60 mg/m(2) on days 1 and 8 of a 21-day schedule. Phase II trials of this regimen are ongoing or planned in lung, head and neck, stomach, esophageal, and pancreatic cancers.